Arsenic is a naturally occurring toxic metalloid element to which prolonged exposure in humans is associated with keratosis, hyperpigmentation, lung and cardiovascular disease, and multiple forms of cancer. Chronically exposed individuals show high variability in symptoms, even among similarly exposed individuals. Host specific factors like genetic variability, body weight, and diet only partially account for this observed variability. In ecosystems where it occurs naturally, arsenic can exist in a variety of organic and inorganic chemical compounds of varying degrees of toxicity. In these environments, biochemical transformations of arsenic are primarily driven by microbial processes. Some microbes also have the ability to incorporate arsenic into their cellular biomass. The gastrointestinal tract (GIT) microbiome of mammals confers numerous important functional benefits to the host organism, many of which are not well understood or characterized. It has also been shown that altering gut microbial communities of mice can change the profile of arsenic transformations that take place in these communities. Preliminary research suggests that the GIT microbiome functions to protect the murine host from ingested arsenic. We have demonstrated that germ-free mice and mice with antibiotic-disrupted GIT microbiomes accumulate more arsenic in host tissues when compared with similarly exposed mice with conventional microbiomes. When the primary host system for detoxifying systemic arsenic is inactivated, mortality is observed in germ-free and antibiotic treated mice, even at low levels of arsenic exposure. The proposed research aims to investigate the function of the human microbiome in arsenic toxicity by leveraging the use of germ-free mice, which can be colonized with the GIT microbiome from a human donor. This research will investigate not only the influence of the human microbiome on host arsenic exposure, but also the mechanisms by which it influences. Arsenic transformations will be measured in germ-free and humanized mice while tracking host health to determine the health impacts of specific transformations in vivo. In order to determine if specific microbial groups increase or decrease the host's exposure to toxic arsenicals, the microbiome of humanized mice will be manipulated while monitoring arsenic transformations and host health. This research will elucidate new functions of the human microbiome relating to arsenic toxicity. There is potential for this project to have immediate impacts on human health interventions.